Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women.

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.

The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients.

Purposes: Most molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and Methods: We collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. Results: PAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. Conclusions: This is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT02326857).

Consenso chileno de diagnóstico y manejo de neoplasias quísticas pancreáticas. Club de páncreas Chile-SCHGE / Chilean consensus on diagnosis and management of pancreatic cystic neoplasms

Pancreatic cystic neoplasms (PCN) are frequently detected on abdominal images performed for non-pancreatic indications. Their prevalence in asymptomatic population ranges from 2.7 to 24.8%, and increases with age. There are several types of pancreatic cysts. Some may contain cancer or have malignant potential, such as mucinous cystic neoplasms, including mucinous cystadenoma (MCN) and intraductal papillary mucinous neoplasms (IPMN). In contrast, others are benign, such as serous cystadenoma (SCA). However, even those cysts with malignant potential rarely progress to cancer. Currently, the only treatment for pancreatic cysts is surgery, which is associated with high morbidity and occasional mortality. The Board of the Chilean Pancreas Club of the Chilean Gastroenterology Society developed the first Chilean multidisciplinary consensus for diagnosis, management, and surveillance of PCN. Thirty experts were invited and answered 21 statements with five possible alternatives: 1) fully agree; 2) partially agree; 3) undecided; 4) disagree and 5) strongly disagree. A consensus was adopted when at least 80% of the sum of the answers "fully agree" and "partially agree" was reached. The consensus was approved by the Board of Directors of the Chilean Pancreas Club for publication.

Perioperative chemotherapy in locally advanced gastric cancer in Chile: from evidence to daily practice.

Gastric cancer (GC) is a leading cause of cancer death in Chile. Although recommended in international guidelines since 2006, perioperative chemotherapy was not available to patients in the public health system in Chile until 2016. We conducted an observational study to assess the feasibility of this strategy in public hospitals in Chile (Observational Study of Perioperative Chemotherapy in Locally Advanced Gastric Cancer - PRECISO). Patients with locally advanced, operable GC were offered to receive preoperative chemotherapy with Epirubicin + Cisplatin + Capecitabine (ECX) for three cycles followed by curative surgery. Staging included abdominal CT scan and laparoscopy if peritoneal carcinomatosis was suspected. Postoperative ECX for three cycles was recommended. Between August 2010 and March 2013, 110 patients were screened and 61 enrolled. Median age was 62 years (23-76 years) and most patients had good performance status at baseline (Eastern Cooperative Oncology Group performance status score (ECOG) 0: 42, ECOG 1: 19). Tumour site was proximal in 32 (52%) and medial and distal in 29 (48%) patients. All but four patients (n = 57, 93%) completed three cycles of preoperative chemotherapy. Fifty-six patients were operated and 54 (89%) had a curative resection. Thirty-three patients (54%) had pT0-2, and 18 (30%) had pN0 tumours, with two patients achieving a complete response. As of 20 December 2020, 39 patients died, 32 due to GC, one within 30 days of surgery, two due to intestinal obstruction at 5 and 3 months after surgery and four due to other causes. Five-year survival rate was 38%. We conclude that perioperative chemotherapy is feasible in public hospitals in Chile and should be offered to patients with locally advanced GC.

Compact and efficient gas diffusion electrodes based on nanoporous alumina membranes for microfuel cells and gas sensors.

This work describes the fabrication, characterization and evaluation of thin gas diffusion electrodes (GDEs) that are capable of electrocatalyzing the reaction of dissolved gases operating at high diffusion limiting current densities and with fast response times. Nanoporous alumina membranes (NAMs) were used as supports of metal electrocatalysts. NAMs were hydrophobized by silanization and coated on one side with Pt, either over the whole alumina surface by sputtering or just onto the pore openings by local chemical deposition. The Pt-modified NAM-based GDEs were evaluated for hydrogen oxidation. They operated by exposing their coated side to the electrolyte solution and the hydrophobic uncoated side to the flowing gas. Due to the NAM hydrophobicity, flooding of the pores by the electrolyte was diminished, so they were quickly filled by the circulating gas. Simulations of the process on single-pore GDEs showed that the dissolved gas diffused into the solution both radially (ideal pore) and linearly (partially flooded pore), reaching the electrocatalyst film placed right around the pore, which guaranteed a fast mass transport. Hydrogen oxidation operated on these NAM-based GDEs at a steady state with limiting current densities as high as 0.5 A cm-2, which were attained in less than 5 s and were proportional to H2 concentrations over a wide range. Thus, their potential use in microfuel cells and gas sensors was demonstrated.

BRCA1 and BARD1 colocalize mainly in the cytoplasm of breast cancer tumors, and their isoforms show differential expression.

BRCA1 has been found to be absent or miss localized in the cytoplasm in a relevant proportion of breast cancer tumors with no germline mutations. BRCA1 main function is in the nucleus, and its interaction with BARD1 is relevant for its nuclear translocation and retention. Our aim was to analyze the sub-cellular localization of BRCA1 and BARD1 in breast cancer tumors, and determine the level of expression of their splice variants BRCA1-Δ11q and BARD1-α and BARD1-ß. BRCA1 and BARD1 expressions were performed by immunohistochemistry and immunofluorescence in 103 breast cancer tumors. Colocalization was determined by confocal microscopy. Transcript variants were determined by qRT-PCR. We found BRCA1 localized in the cytoplasm with BARD1 in 51.4 % of tumors. An exclusive nuclear localization of both proteins was observed in 7/103 tumors (6.8 %). Indeed, these tumors displayed an apparent nucleolar colocalization of BARD1 and BRCA1. In relation to splice variants, there is a tendency to an overexpression of BARD1-α mRNA (30 % of tumors) and a decreased expression of BARD1-ß (41 %). BRCA1 full-length was downregulated in 63 % of tumors, and 37 % showed BRCA1-Δ11q variant overexpressed. Our findings contribute to a better understanding of the expression and sub-cellular localization of BRCA1 in breast cancer tumors. Interaction of BRCA1 and BARD1 seems to be not affected in 58.2 % of tumors, which showed colocalization of both proteins. The absence of BRCA1 in 41 % of tumors reveals a BRCAness phenotype, constituting an excellent marker for therapy sensitivity, to platinum drugs or PARP inhibitors.

Silencing of tumor suppressor genes RASSF1A, SLIT2, and WIF1 by promoter hypermethylation in hereditary breast cancer.

Promoter hypermethylation is gaining strength as one of the main mechanisms through which tumor suppressor genes are silenced during tumor progression. Three tumor suppressor genes are frequently found methylated in their promoter, in concordance with absence of expression, RASSF1A, SLIT2, and WIF1. In addition, a previous array-CGH analysis from our group showed that these genes are found in deleted genomic regions observed in hereditary breast cancer tumors. In the present work we analyzed the methylation status of these three tumor suppressor gene promoters in 47 hereditary breast cancer tumors. Promoter methylation status analysis of hereditary breast tumors revealed high methylation frequencies for the three genes (67% RASSF1A, 80% SLIT2, and 72% WIF1). Additionally, the presence of methylated PCR products was associated with absence of protein expression for the three genes and statistically significant for RASSF1A and WIF1. Interestingly, methylation of all the three genes was found in 4 out of 6 grade I invasive ductal carcinoma tumors. Association between RASSF1A methylation and DCIS tumors was found. These results suggest that silencing of these tumor suppressor genes is an early event in hereditary breast cancer, and could be a marker for pre-malignant phenotypes.

Alteración de la fertilidad masculina por hiperplasia suprarrenal congénita: Azoospermia reversible con terapia de glucocorticoide / Congenital adrenal hyperplasia causing male infertility: Report of one case

In males, congenital adrenal hyperplasia due to 21 hydroxylase deficiency is associated to normal fertility or infertility caused by a hypogonadotrophic hypogonadism (HH) or gonadal damage caused by intratesticular adrenal remnants. We report a 29-year-old male with azoospermia, without any important personal or family background. Physical examination was normal, his height was 150 cm and his testicular volume was 10 ml (normal 15 to 25 ml). Laboratory showed a normal testosterone and FSH and LH in the low normal limit. These results discarded a HH, whose diagnostic requirements are a low testosterone and inadequately normal or low gonadotrophins. A testicular biopsy was informed as compatible with HH. A 21 hydroxylase deficiency was suspected and confirmed with extremely high levels of 17 hydroxyprogesterone at baseline and after stimulation with fast acting ACTH. Clomiphene citrate did not increase testosterone or gonatrophin levels. Testicular ultrasound discarded the presence of adrenal nodules. Betametasone therapy resulted in a normal testicular development, normalization of sperm count, reduction of 17 hydroxyprogesterone and testosterone levels with an ulterior rise of the latter. Spontaneous paternity was achieved twice. It must be remembered that in cases of azoospermia due to congenital adrenal hyperplasia, testosterone produced by adrenal glands hinders the laboratory diagnosis of HH.

[Congenital adrenal hyperplasia causing male infertility. Report of one case]. / Alteración de la fertilidad masculina por hiperplasia suprarrenal congénita. Azoospermia reversible con terapia de glucocorticoide.

In males, congenital adrenal hyperplasia due to 21 hydroxylase deficiency is associated to normal fertility or infertility caused by a hypogonadotrophic hypogonadism (HH) or gonadal damage caused by intratesticular adrenal remnants. We report a 29-year-old male with azoospermia, without any important personal or family background. Physical examination was normal, his height was 150 cm and his testicular volume was 10 ml (normal 15 to 25 ml). Laboratory showed a normal testosterone and FSH and LH in the low normal limit. These results discarded a HH, whose diagnostic requirements are a low testosterone and inadequately normal or low gonadotrophins. A testicular biopsy was informed as compatible with HH. A 21 hydroxylase deficiency was suspected and confirmed with extremely high levels of 17 hydroxyprogesterone at baseline and after stimulation with fast acting ACTH. Clomiphene citrate did not increase testosterone or gonatrophin levels. Testicular ultrasound discarded the presence of adrenal nodules. Betametasone therapy resulted in a normal testicular development, normalization of sperm count, reduction of 17 hydroxyprogesterone and testosterone levels with an ulterior rise of the latter. Spontaneous paternity was achieved twice. It must be remembered that in cases of azoospermia due to congenital adrenal hyperplasia, testosterone produced by adrenal glands hinders the laboratory diagnosis of HH.

HPV genotyping from invasive cervical cancer in Chile.

OBJECTIVE: To determine the prevalence rates of the different HPV types in cervical cancer lesions in Chile to facilitate the development of prophylactic human papillomavirus (HPV) vaccines effective for that country. METHOD: Biopsy samples of 312 cervical cancer lesions were assessed for HPV type by reverse-line blotting assay. RESULTS: HPV DNA was found in 94.2% of the lesions, 67.2% harboring 1 viral type and the remainder harboring more than 1 type. HPV-16 was the most frequent type in single infections (50.5%), followed by HPV-18 (7.8%), HPV-31 (2.4%), and HPV-45 (2.0%). HPV-16 was also present in 98.7% of dual and multiple infections, its most frequent association being with HPV-18. CONCLUSIONS: HPV types 16, 18, 31, and 45, alone or combined with other types, were observed in the biopsy samples of up to 80.5% of cervical cancer lesions.

Oncogenic hypophosphatemic osteomalacia associated with a nasal hemangiopericytoma.

We report a patient with a nasal hemangiopericytoma associated with an oncogenic hypophosphatemic osteomalacia (OHO). This syndrome results from tumor products that decrease renal tubular phosphate resorption, leading to the osteomalacia. This patient presented with classic bone manifestations of osteomalacia and a nasal tumor. Laboratory studies performed before the first resection of the tumor included normal serum calcium, hypophosphatemia due to decreased tubular reabsorption of phosphate, and an undetectable serum 1,25 dihydroxy vitamin D level. Serum parathormone level was normal. Anterior iliac crest bone biopsy showed characteristic signs of osteomalacia that included increased osteoid and delayed mineralization. A partial resection of the nasal tumor was performed. After the first surgery the patient showed detectable serum level of 1,25 dihydroxy vitamin D, and transient normalization of the tubular reabsorption of phosphate. The patient was also treated with phosphate supplements and vitamin D with transient control of her clinical manifestations and improvement of the radiographic signs of osteomalacia. Three months after surgery, the serum level of 1,25 dihydroxy vitamin D level again became undetectable. After selective embolization of the tumor, followed by an apparent complete tumor resection and postoperative radiation therapy, her hypophosphatemia and decreased phosphate tubular reabsorption persisted. Therefore, biochemical changes associated with hemangiopericytoma induced OHO may persist even after apparent total tumor resection. Clinicians should be aware of the oncogenic basis for some osteomalacia, as seen in this patient.

Tumor de Wilms: histopatología y pronóstico / Wilms' tumor: histopathology and prognosis

Se analizan 40 casos de tumor de Wilms con el objeto de establecer la relación existente entre los estadios clínicos, la histopatología del tumor y el pronóstico del mismo, así como la frecuencia de presentación de cada uno de los subtipos histológicos. El mayor porcentaje de nuestros casos correspondían al tipo histológico mixto, seguido de la variedad epitelial, blastematosa y estromatosa. El 77.5% de los casos correspondían a subtipos histológicos de "pronóstico favorable" y el 22% a subtipos histológicos de "pronóstico desfavorable" (con anaplasia o componentes sarcomatosos). Se observó una mortalidad menor en los estadios I y II de la clasificación del NWTS, los que a su vez muestran un mayor porcentaje de subtipos histológicos de pronóstico favorable. Se observó un peor pronóstico en los pacientes cuyos tumores correspondían a la variedad sarcomatosa o que presentaban anaplasia. En ellos la mortalidad fue de un 55.5% en contraposición con los otros subtipos, en los cuales esta fue de un 25.5%. Todos los casos con anaplasia correspondían al tipo mixto, sin que se observaran diferencias significativas en la mortalidad de este grupo entre los subtipos con o sin anaplasia. Los resultados de este estudio confirman la importancia de que la clasificación histológica del tumor de Wilms, en grupos de pronóstico favorable y desfavorable, sea parte integral del protocolo de tratamiento de los pacientes con este tumor